Process for preparing terbinafine by using platinum as catalyst

ABSTRACT

A process for the preparation of terbinafine, comprising the reaction of a compound of formula (II), or a salt thereof, wherein X is a leaving group, with tert-butylacetylene, in the presence of a platinum catalyst.

FIELD OF THE INVENTION

The present invention belongs to the field of pharmaceutical chemistryand relates to a novel process for preparing terbinafine and thepharmaceutically acceptable salts thereof.

TECHNOLOGICAL BACKGROUND

Terbinafine, or(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine,is a known medicament with antifungal activity for topical use and hasbeen first disclosed in EP 024587. The (E) stereoisomer of said compoundis biologically active. In view of the interest of this product, variousalternative processes for its production, more advantageous than thosedisclosed in EP 024587, have been developed, particularly thosedisclosed in EP 421302, WO 02/02503 and EP 1236709.

EP 421302 and WO 02/02503 disclose processes in which the last syntheticstep comprises the reaction ofN-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine withtert-butylacetylene, in the presence of an organic amine and catalyticamounts of palladium salts and copper(I) iodide. Palladium compoundsconventionally used for the coupling reaction known as “palladiumcatalyst-cross coupling reaction” are used as palladium catalysts.Examples of the palladium compounds reported in EP 421302 and WO02/02503 comprise palladium-tertiary phosphine complexes, combinationsof a palladium salt with a tertiary phosphine and a combination of apalladium complex with a tertiary phosphine. The processes described insaid documents afford terbinafine in good yields but they have someremarkable drawbacks: for instance, the final product is contaminated bypalladium and decomposition products of the palladium-phosphorouscomplexes, which have to be removed with cumbersome, expensivepurification processes, for example by liquid column chromatography.

The process disclosed in EP 1236709 has overcome the drawbacks connectedwith the use of palladium catalysts, by reactingN-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine withtert-butylacetylene in alkali medium in the presence of copper(I) saltsonly. This process affords terbinafine free from catalyst contaminationsin good yield, but it requires long reaction times, which do notsuitably meet the requirements for the industrial production on a largescale.

As a consequence, there is the need for alternative processes for thepreparation of terbinafine on an industrial scale, which overcome thedrawbacks of the known processes.

The inventors of the present invention have surprisingly found a novelprocess for the preparation of terbinafine, which can be carried out incomparatively short reaction times and affords a product free fromcatalyst contaminations and other reaction by-products, and moreover insignificantly quantitative yield and improved stereoisomeric (E/Z)ratio.

DETAILED DISCLOSURE OF THE INVENTION

The present invention relates to a process for preparing terbinafine, ora pharmaceutically acceptable salt thereof, comprising reacting acompound of formula (II), or a salt thereof,

-   -   wherein X is a leaving group,    -   with tert-butylacetylene, in the presence of a platinum        catalyst.

The leaving group X is a conventional leaving group, for example ahalogen atom, in particular chlorine, bromine or iodine, aperfluoroalkylsulfonic group, in particular perfluorooctylsulfonic orperfluorobutylsulfonic, or an an esterified hydroxy group, e.g. a—O-mesyl or —O-tosyl group.

A salt of a compound of formula (II) is a salt with an organic orinorganic acid and is a further object of the invention. Examples ofsalts of a compound of formula (II) are hydrochloride, hydrobromide,sulfate, fumarate, formate, acetate, propionate, tartrate, citrate,oxalate, malonate, maleate, methanesulfonate, paratoluenesulfonate orbenzoate or a derivative thereof wherein the phenyl ring is optionallysubstituted with one or two groups independently selected from chlorine,bromine, iodine, hydroxy, nitro, C₁-C₆ alkyl and C₁-C₆ alkoxy. Apreferred salt isN-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine oxalate.

The reaction between a compound of formula (II), or a salt thereof, andtert-butylacetylene is carried out in an organic solvent, in thepresence of a platinum catalyst and a basic agent. The same reaction canbe carried out in the presence of additional amounts of a coppercompound.

The platinum catalyst is platinum metal or a derivative thereof, forexample platinum acetylacetonate, platinum bis(benzonitrile)dichloride,platinum oxide, a platinum halide, such as platinum chloride, bromideand iodide, or platinum acetate, in particular, platinum chloride orplatinum metal, the latter preferably on an inert support, such ascarbon, silica or alumina, preferably carbon. A particularly preferredexample of catalyst is platinum metal on a carbon support, e.g.charcoal, with platinum content from about 1% to about 10%, preferablyfrom about 5% to about 10%.

A copper compound is for example copper (I) chloride, copper (I)bromide, copper (I) iodide, copper acetate or copper (I) oxide,preferably copper (I) iodide.

The organic solvent can be an organic protic solvent, such as methanolor ethanol; a halogenated hydrocarbon, such as chloroform ordichloromethane; an aromatic hydrocarbon, such as benzene or toluene; anether, such as diethyl ether, tetrahydrofuran or dioxane; or an organicaprotic solvent, such as dimethylformamide, dimethyl sulfoxide oracetonitrile.

The basic agent can be an organic or inorganic base. Examples of organicbase are trimethylamine, triethylamine, pyridine, piperidine,butylamine, N,N-dimethylformamide and 4-dimethylaminopyridine,preferably piperidine or butylamine. Examples of inorganic base aresodium or potassium hydroxide, bicarbonate and carbonate.

The organic base itself, for example piperidine, pyridine ortriethylamine, can act as the organic solvent when used in a largeexcess, typically in amounts approx. from 3 to 20 equivalents perequivalent of a compound of formula (II), or a salt thereof.

The coupling reaction between tert-butylacetylene and a compound offormula (II), or a salt thereof, can be carried out using stoichiometricamounts of the two reagents, or a tert-butylacetylene excess, forexample approximately from 1 to 2, preferably approximately 1.3-1.6,equivalents of tert-butylacetylene per equivalent of a compound offormula (II), or a salt thereof.

The amount of platinum catalyst is preferably approximately equal to orlower than 10% molar with respect to a compound of formula (II), or asalt thereof, typically lower than approximately 3%-10% molar.

The amount of a copper compound is preferably a catalytic amount and itsmolar amount is usually twice the molar amount of platinum catalyst.

The reaction is typically carried out adding tert-butylacetylene to adispersion of compound of formula (II), or a salt thereof, platinumcatalyst and basic agent in the organic solvent, optionally also addinga copper compound as defined above. The reaction is carried out withstirring and preferably under inert atmosphere, for example undernitrogen atmosphere. When the organic base itself, for examplepiperidine, is used as the organic solvent, tert-butylacetylene is addedto a dispersion of compound of formula (II), or a salt thereof, platinumcatalyst and optionally copper compound in piperidine. The reactiontemperature can range from about 0° C. to about 80° C., preferably fromabout 20° C. about 90° C., more preferably from about 30° C. to about80° C. Reaction times approximately range about from 3 to 10 hours,preferably from 4 to 7 hours.

After completion of the reaction, terbinafine is recovered from thereaction mixture through a series of steps comprising:

-   -   a) treatment of the reaction mixture with a mixture of water and        an organic solvent in which terbinafine is soluble, for example        toluene;    -   b) separation of the platinum catalyst, when use of platinum        metal catalyst on an inert support is made;    -   c) neutralization of the mixture by treatment with a suitable        acid, for example hydrochloric acid; and    -   d) separation of the organic phase containing terbinafine and        evaporation of the organic solvent, to obtain crude terbinafine        in very good yield.

A pharmaceutically acceptable salt of terbinafine is for example anaddition salt with a mineral or organic acid, such as hydrochloric,sulfuric, nitric or malic acid. terbinafine can be converted into apharmaceutically acceptable salt thereof by known methods, e.g. asreported in EP 1236709.

The process of the invention surprisingly provides terbinafine withenriched stereoisomeric E/Z ratio than the one of the starting compoundof formula (II), thus it allows preparation of terbinafine assubstantially pure (E)-form even starting from a compound of formula(II) wherein the E/Z ratio is lower than or equal to 95%. Moreover suchterbinafine pure (E)-form is endowed with high purity, being inparticular free from catalyst residues and other by-products. Inparticular, when the coupling reaction is carried out using a compoundof formula (II) in a salified form, highly pure terbinafine (E)-form isalready obtained at this step. Anyway, if the case, subsequent isolationof pure terbinafine pure (E)-form can be carried out according to knownmethods, for example as reported in EP 1236709.

A further object of the invention is pure terbinafine, namely(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine,or a pharmaceutically acceptable salt thereof, in particular thehydrochloride, as pure (E)-form and free from catalyst residues, asobtainable by the process of the invention.

By “pure” is meant having a purity equal to or greater than 99.5%.

By “pure (E)-form” is meant having a stereoisomeric (E)-form purityequal to or greater than 99.5.

By “free from catalyst residues” is meant a residue amount in platinumcatalyst and/or a copper compound lower than 1 p.p.m.

From what described above and from the results reported in theexperimental section, it will be appreciated that the novel process forthe preparation of terbinafine affords this product free from catalystand by-products contaminants, and also in a significantly quantitativeyield and with very good stereoisomeric (E/Z) ratio, in particular alsoas pure (E)-form, already at the step yielding crude terbinafine.

The process of the invention is particularly suitable for the industrialproduction of terbinafine, as reaction times are comparatively short andthe platinum catalyst can be easily recovered quantitatively, thusremarkably decreasing production costs. Furthermore, the processrequires no chromatographic purifications which are known to be timeconsuming, complex and hardly suitable for the industrial production.

Tert-butylacetylene and the compound of formula (II) are known productsor can be prepared according to known methods, for example as reportedin EP 421303. A salt of a compound of formula (II) can be obtained bysalification of a compound of formula (II) with organic or inorganicacids according to known methods, for example as reported herein.

The following examples further illustrate the invention.

EXAMPLE 1 Preparation of Terbinafine

A 50 ml 3-necked round-bottom flask equipped with condenser, thermometerand magnetic stirrer, under nitrogen atmosphere, is loaded with 10 g ofN-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine (40.69 mmoles)(E/Z=80/20), 15.8 g of 10% Pt/C with 50% humidity (4.07 mmoles), 1.54 gof CuI (8.14 mmoles), 55.4 g of piperidine (651.1 mmoles) at roomtemperature. The mixture is heated under stirring to approx. 80° C.inner temperature for 30′, then cooled to about 40° C. and 4.68 g oft-butylacetylene (56.96 mmoles) is dropped therein.

The reaction mixture is kept at this temperature for 4 hours, thencooled at room temperature and diluted with 80 ml of toluene and 60 mlof water. Stirring is continued for about 15′, then the mixture isfiltered through Celite® and filtration mother liquors are acidifiedunder stirring with 61.9 g of 37% HCl (610.37 mmoles).

The phases are separated and the toluene phase is evaporated undervacuum at 50° C. to obtain 12.11 g of an oily residue consisting of 11.5g of terbinafine (95% HPLC purity) corresponding to 97% molar yield. Theresulting product has m.p. 193÷194° C. (E/Z=85/15) and the structure isconsistent with ¹HNMR and MS spectra.

¹HNMR (CDCl₃) δ (ppm): 1.23 (s, 9H); 2.60 (d, 3H); 3.72 (m, 2H); 4.65(m, 2H); 5.85 (d, 1H); 6.34 (m, 1H); 7.52÷8.11 (m, 7H).

MS (EI 70 eV) m/e: 291, 276, 234, 196, 150, 141, 115.

EXAMPLE 2 Preparation of Terbinafine

A 50 ml 3-necked round-bottom flask equipped with condenser, thermometerand magnetic stirrer, under nitrogen atmosphere, is loaded with 2.05 gof N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine oxalate(6.1 mmoles) (E/Z=80/20), 2.38 g of 10% Pt/C with 50% humidity (0.7mmoles), 0.26 g of CuI (1.4 mmoles), 7.8 g of piperidine (91.5 mmoles)at room temperature. The mixture is heated under stirring to approx. 80°C. inner temperature for 30′, then cooled to about 40° C. and 1.02 g oft-butylacetylene (12.5 mmoles) is dropped therein.

The reaction mixture is kept at this temperature for 4 hours, thencooled at room temperature and diluted with 50 ml of toluene and 25 mlof water. Stirring is continued for about 15′, then the mixture isfiltered through Celites® and filtration mother liquors are acidifiedunder stirring with 11.5 g of 37% HCl (116.7 mmoles).

The phases are separated and the toluene phase is evaporated undervacuum at 50° C. to obtain 1.76 g of an oily residue consisting of 1.70g of terbinafine (96.5% HPLC purity) (5.86 mmoles) corresponding to95.6% molar yield. The resulting product has m.p. 193÷195° C.(E/Z=88/12) and the structure is consistent with ¹HNMR and MS spectra.

¹HNMR (CDCl₃) δ (ppm): 1.22 (s, 9H); 2.61 (d, 3H); 3.72 (m, 2H); 4.65(m, 2H); 5.87 (d, 1H); 6.34 (m, 1H); 7.52÷8.10 (m, 7H).

MS (EI 70 eV) m/e: 291, 276, 234, 196, 150, 141, 115.

EXAMPLE 3 Preparation of Terbinafine

A 100 ml 3-necked round-bottom flask equipped with condenser,thermometer and magnetic stirrer, under nitrogen atmosphere, is loadedwith 10 g of N-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine(40.69 mmoles) (E/Z=80/20), 15.8 g of 10% Pt/C with 50% humidity (4.07mmoles), 1.54 g of CuI (8.14 mmoles), 3.24 g of pyridine (41.0 mmoles)and 40 ml of toluene, at room temperature. The mixture is heated understirring to approx. 80° C. inner temperature for 30′, then cooled toabout 40° C. and 4.68 g of t-butylacetylene (56.96 mmoles) is droppedtherein.

The reaction mixture is kept at this temperature for 6 hours, thencooled at room temperature and diluted with 40 ml of water. Stirring iscontinued for about 15′, then the mixture is filtered through Celite®and filtration mother liquors are acidified under stirring with 4.5 g of37% HCl (0.31 mmoles).

The phases are separated and the toluene phase is evaporated undervacuum at 50° C. to obtain 11.9 g of an oily residue consisting of 11.3g of terbinafine (94.9% HPLC purity) corresponding to 95% molar yield.The resulting product has m.p. 193÷194° C. (E/Z=83/17) and the structureis consistent with ¹HNMR and MS spectra.

¹HNMR (CDCl₃) δ (ppm): 1.23 (s, 9H); 2.62 (d, 3H); 3.72 (m, 2H); 4.65(m, 2H); 5.85 (d, 1H); 6.33 (m, 1H); 7.52÷8.11 (m, 7H).

MS (EI 70 eV) m/e: 291, 276, 234, 196, 150, 141, 115.

EXAMPLE 4 Preparation of Terbinafine

A 50 ml 3-necked round-bottom flask equipped with condenser, thermometerand magnetic stirrer, under nitrogen atmosphere, is loaded with 10 g ofN-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine (40.69 mmoles)(E/Z=80/20), 1 g of PtCl₂ (3.76 mmoles), 1.54 g of CuI (8.14 mmoles),55.4 g of piperidine (650.6 mmoles) at room temperature. The mixture isheated under stirring to approx. 80° C. inner temperature for 30′, thencooled to about 40° C. and 4.68 g of t-butylacetylene (56.96 mmoles) isdropped therein.

The reaction mixture is kept at this temperature for 4 hours, thencooled at r.t. and diluted with 40 ml of toluene and 80 ml of water.Stirring is continued for about 15′, then the mixture is filteredthrough Celite® and filtration mother liquors are acidified understirring with 56 g of 37% HCl (570 mmoles).

The phases are separated and the toluene phase is evaporated undervacuum at 50° C. to obtain 13.0 g of an oily residue consisting of 11.5g of terbinafine (88% HPLC purity) (39.4 mmoles) corresponding to 96.9%molar yield. The resulting product has m.p. 193÷194° C. (E/Z=85/15) andthe structure is consistent with ¹HNMR and MS spectra.

¹HNMR (CDCl₃) δ (ppm): 1.23 (s, 9H); 2.60 (d, 3H); 3.72 (m, 2H); 4.65(m, 2H); 5.85 (d, 1H); 6.34 (m, 1H); 7.52÷8.11 (m, 7H).

MS (EI 70 eV) m/e: 291, 276, 234, 196, 150, 141, 115.

EXAMPLE 5 Preparation ofN-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine oxalate

A 500 ml 4-necked round-bottom flask equipped with thermometer andmagnetic stirrer, under nitrogen atmosphere, is loaded with 80 g ofN-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine (325 mmoles)(E/Z=80/20) and 317 g of methanol at room temperature. The resultingsolution is added with 29.3 g of oxalic acid (325 mmoles), keepingstirring for 15′, then the precipitate is filtered and the product iswashed with methanol on the filter. 94.0 g ofN-(3-chloro-2-propenyl)-N-methyl-1-naphthalene-methanamine oxalate(279.9 mmoles) are obtained, 86% (E/Z=80/20) molar yield.

¹HNMR (DMSO-d₆) δ (ppm): 2.33 (s, 3H); 3.44 (d, 2H); 4.23 (s, 2H); 6.18(m, 1H); 6.57 (d, 1H); 7.45÷8.25 (m, 7H).

¹³CNMR (DMSO-d₆) δ (ppm): 163.55; 134.15; 132.56; 131.31; 129.73;129.22; 128.08; 127.06; 126.68; 126.0; 124.93; 124.11, 57.53; 56.24.

EXAMPLE 6 Preparation of Terbinafine

A 50 ml 3-necked round-bottom flask equipped with condenser, thermometerand magnetic stirrer, under nitrogen atmosphere, is loaded with 3 g ofN-(3-chloro-2-propenyl)-N-methyl-1-naphthalenemethanamine (12.0 mmoles)(E/Z=98/2), 0.27 g of Pt/C 10% (about 50% humidity) (0.069 mmoles),0.027 g of CuI (0.14 mmoles), 3.11 g of piperidine (36 mmoles) at roomtemperature. The mixture is heated under stirring to approx. 80° C.inner temperature for 30′, then cooled to about 40° C. and 1.29 g oft-butylacetylene (16 mmoles) is dropped therein.

The reaction mixture is heated at 80° C. and is kept in these conditionsfor 3 hours, then is cooled at r.t. and diluted with 40 ml of tolueneand 80 ml of water. Stirring is continued for about 15′, then themixture is filtered through Celite® and filtration mother liquors areacidified under stirring with 3.1 g of 37% HCl (31.6 mmoles).

The phases are separated and the toluene phase is evaporated undervacuum at 50° C. to obtain 3.60 g of an oily residue consisting of 3.42g of terbinafine (99.5% HPLC purity) (11.76 mmoles) corresponding to 98%molar yield. The resulting product has m.p. 193÷194° C. (E/Z=99.5:0.5),a content of catalyst residues lower than 1 p.p.m. and the structure isconsistent with ¹HNMR and MS spectra.

¹HNMR (CDCl₃) δ (ppm): 1.23 (s, 0.9H); 2.60 (d, 3H); 3.72 (m, 2H); 4.65(m, 2H); 5.85 (d, 1H); 6.34 (m, 1H); 7.52÷8.11 (m, 7H).

MS (EI 70 eV) m/e: 291, 276, 234, 196, 150, 141, 115.

EXAMPLE 7 Terbinafine Hydrochloride

Terbinafine as obtained according to one of the above examples isreacted in acetone with a stoichiometric amount of 37% molarhydrochloric acid. Crystallization is obtained by seeding with pureterbinafine hydrochloride, cooling to −10° C. After one hour, themixture is filtered and the solid is washed with acetone, then dried toobtain pure terbinafine hydrochloride as a white solid having 99.9% HPLCpurity (E/Z=100:0) and a content of catalyst residues lower than 1p.p.m.

1. A process for the preparation of terbinafine, or a pharmaceuticallyacceptable salt thereof, comprising reacting a compound of formula (II),or a salt thereof,

wherein X is a leaving group, with tert-butylacetylene, in the presenceof a platinum catalyst.
 2. A process as claimed in claim 1, wherein theplatinum catalyst is selected from the group consisting of platinummetal, platinum acetylacetonate, platinum bis(benzonitrile)dichloride,platinum oxide, platinum halide and platinum acetate.
 3. A process asclaimed in claim 1, wherein said reaction is carried out in an organicsolvent, in the presence of a basic agent and a catalytic amount acopper compound.
 4. A process according to claim 3, wherein the coppercompound is copper (I) chloride, copper (I) bromide, copper (I) iodide,copper acetate or copper (I) oxide.
 5. A process according to claim 3,wherein the organic solvent is the basic agent itself.
 6. A process asclaimed in claim 5, wherein the basic agent is an organic or inorganicbase.
 7. A process, according to claim 1, wherein the reaction iscarried out in the presence of platinum chloride or platinum metal on aninert support; in the presence of a catalytic amount of copper (I)iodide, in the presence of a basic agent.
 8. A process according toclaim 7, wherein the molar amount of copper (I) iodide is twice themolar amount of platinum catalyst.
 9. Terbinafine, or a pharmaceuticallyacceptable salt thereof, having a purity equal to or greater than 99.5%.10. Terbinafine, or a pharmaceutically acceptable salt thereof, as pure(E)-form.
 11. Terbinafine, or a pharmaceutically acceptable saltthereof, free from catalyst residues.
 12. A compound of formula (II), asclaimed in claim 1, in the form of an organic or inorganic acid additionsalt thereof.
 13. A process as claimed in claim 2, wherein said reactionis carried out in an organic solvent, in the presence of a basic agentand a catalytic amount a copper compound.